Phosphoinositide-3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate phosphoinositols on the 3′-OH to generate PI3P (phosphatidylinositol 3-phosphate), PI-3,4-P2 and PI3,4,5-P3. One class of PI3Ks are stimulated by growth factors (Katso et al. Annu. Rev. Cell Dev. Biol. 2001;14:615–675) and include PI3Kα, PI3Kβ, and PI3Kδ(Vanhaesebroeck et al. Proc. Natl. Acad. Sci., U.S.A., 1997;94:4330–4335; Katso et al., 2001). A separate class of PI3Ks are activated by G-protein coupled receptors and include PI3Kγ. The growth-factor stimulated PI3Ks (e.g., PI3Kα), have been implicated in cellular proliferation and cancer (reviewed in Katso et al., 2001; and Vivanco and Sawyers Nature Reviews, 2002;2:489–501). PI3Kγ has been demonstrated to be involved in signaling cascades. For example, PI3Kγ is activated in response to ligands such as C5a, fMLP, ADP, and IL-8. In addition, PI3Kγ has been implicated in immune diseases (Hirsch et al. Science 2000;287: 1049–1053). PI3Kγ null macrophages show a reduced chemotactic response and a reduced ability to fight inflammation (Hirsch et al. 2000). Furthermore, PI3Kγ has also been implicated in thrombolytic diseases (e.g., thromboembolism, ischemic diseases, heart attacks, and stroke) (Hirsch et al. FASEB J. 2000;15(11):2019–2021; and Hirsch et al. FASEB J., Jul. 9, 2001;10.1096/fj.00-0810fje (cited herein as Hirsch et al., 2001).
Inhibitors of members of the PI3Ks are being developed for the treatment of human disease (see e.g., WO 01/81346; WO 01/53266; and WO 01/83456). Therefore, there is a need in the art for compounds that can inhibit PI3Ks for use as pharmaceutical agents.